Effect of active smoking on the human bronchial epithelium transcriptome

Twenty-four SAGE profiles of the bronchial epithelium of eight current, twelve former and four never smokers were generated and analyzed. In total, 3,111,471 SAGE tags representing over 110 thousand potentially unique transcripts were generated, comprising the largest human SAGE study to date. We identified 1,733 constitutively expressed genes in current, former and never smoker transcriptomes. We have also identified both reversible and irreversible gene expression changes upon cessation of smoking; reversible changes were frequently associated with either xenobiotic metabolism, nucleotide metabolism or mucus secretion. Increased expression of TFF3, CABYR, and ENTPD8 were found to be reversible upon smoking cessation. Expression of GSK3B, which regulates COX2 expression, was irreversibly decreased. MUC5AC expression was only partially reversed. Validation of select genes was performed using quantitative RT-PCR on a secondary cohort of nine current smokers, seven former smokers and six never smokers.Expression levels of some of the genes related to tobacco smoking return to levels similar to never smokers upon cessation of smoking, while expression of others appears to be permanently altered despite prolonged smoking cessation. These irreversible changes may account for the persistent lung cancer risk despite smoking cessation.Lung cancer has the highest mortality rate among all types of malignancies, accounting for approximately 29% of all cancer-related deaths in the United States [1]. It has been estimated that in 2006 alone, the number of new lung cancer cases will exceed 174,000 and approximately 163,000 people will die of this disease [1]. Tobacco smoking accounts for 85% of the lung cancers. Former heavy smokers remain at an elevated risk for developing lung cancer even years after they stop smoking [2,3]. Fifty percent of newly diagnosed lung cancer patients are former smokers [4]. It is therefore important to understand the effects of tobacco smoking on the